This invention relates to a series of pyrazolo[4,3-d]pyrimidin-7-ones, which inhibit cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterases (cGMP PDEs). More notably, the compounds of the invention are potent and selective inhibitors of type 5 cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate phosphodiesterase (cGMP PDE5) and have utility therefore in a variety of therapeutic areas.
In particular, the compounds are of value in the treatment of male erectile dysfunction (MED) and female sexual dysfunction (FSD) but, clearly, will be useful also for treating other medical conditions for which a potent and selective cGMP PDE5 inhibitor is indicated. Such conditions include premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, conditions of reduced blood vessel patency, e.g. post-percutaneous transluminal coronary angioplasty (post-PTCA), peripheral vascular disease, stroke, bronchitis, allergic asthma, chronic asthma, allergic rhinitis, glaucoma and diseases characterised by disorders of gut motility, e.g. irritable bowel syndrome (IBS).
Other conditions which may be mentioned include pre-eclampsia, Kawasaki""s syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer""s disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure and hypoxic vasoconstriction.
Particularly preferred conditions include MED and FSD.
Thus the invention provides compounds of formulae (IA) and (IB): 
or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity,
wherein R1 is C1 to C3 alkyl optionally substituted with phenyl, Het or a N-linked heterocyclic group selected from piperidinyl and morpholinyl; wherein said phenyl group is optionally substituted by one or more substituents selected from C1 to C4 alkoxy; halo; CN; CF3, OCF3 or C1 to C4 alkyl wherein said C1 to C4 alkyl group is optionally substituted by C1 to C4 haloalkyl or C1 to C4 haloalkoxy either of which is substituted by one or more halo atoms;
R2is C1 to C6 alkyl;
R13 is OR3 or NR5R6;
R3 is C1 to C6 alkyl optionally substituted with one or two substituents selected from C3 to C6 cycloalkyl, OH, C1 to C4 alkoxy, benzyloxy, NR5R6, phenyl, furanyl and pyridinyl; C3 to C6 cycloalkyl; 1-(C1 to C4 alkyl)piperidinyl; tetrahydrofuranyl or tetrahydropyranyl; and wherein the C1 to C6 alkyl and C1 to C4 alkoxy groups may optionally be terminated by a haloalkyl group such as CF3;
R4 is SO2NR7R8;
R5 and R6 are each independently selected from H and C1 to C4 alkyl optionally substituted with C3 to C5 cycloalkyl or C1 to C4 alkoxy, or, together with the nitrogen atom to which they are attached, form an azetidinyl, pyrrolidinyl, piperidinyl or morpholinyl group;
R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group optionally substituted with one or two C1 to C4 alkyl groups and optionally in the form of its 4-N-oxide;
R10 is H; C1 to C4 alkyl optionally substituted with one or two substituents selected from OH, NR5R6, CONR5R6, phenyl optionally substituted with C1 to C4 alkoxy, benzodioxolyl and benzodioxanyl; C3 to C6 alkenyl; pyridinyl or pyrimidinyl;
and Het is a C-linked 6-membered heterocyclic group containing one or two nitrogen atoms, optionally in the form of its mono-N-oxide, or a C-linked 5-membered heterocyclic group containing two or three nitrogen atoms, wherein either of said heterocyclic groups is optionally substituted with C1 to C4 alkyl, C1 to C4 alkoxy or NHR15 wherein R15 is H, C1 to C4 alkyl or C1 to C4 alkanoyl.
In the above definition, unless otherwise indicated, alkyl, alkoxy and alkenyl groups having three or more carbon atoms, and alkanoyl groups having four or more carbon atoms, may be straight chain or branched chain. The term halo atom includes, Cl, Br, F, and I. Haloalkyl and haloalkoxy are preferably CF3 and OCF3 respectively.
The compounds of formulae (IA) and (IB) may contain one or more chiral centres and therefore can exist as stereoisomers, i.e. as enantiomers or diastereoisomers, as well as mixtures thereof. The invention includes both the individual stereoisomers of the compounds of formulae (IA) and (IB) and any mixture thereof. Separation of diastereoisomers may be achieved by conventional techniques, e.g. by fractional crystallisation or chromatography (including HPLC) of a diastereoisomeric mixture of a compound of formula (IA) or (IB) or a suitable salt or derivative thereof. An individual enantiomer of a compound of formula (IA) or (IB) may be prepared from a corresponding optically pure intermediate or by resolution, either by HPLC of the racemate using a suitable chiral support or, where appropriate, by fractional crystallisation of the diastereoisomeric salts formed by reaction of the racemate with a suitable optically active acid or base.
The compounds of formulae (IA) and (IB) may also exist in tautomeric forms and the invention includes both mixtures thereof and the individual tautomers.
Also included in the invention are radiolabelled derivatives of compounds of formulae (IA) and (IB) which are suitable for biological studies.
The pharmaceutically or veterinarily acceptable salts of the compounds of formulae (IA) and (IB) which contain a basic centre are, for example, non-toxic acid addition salts formed with inorganic acids such as hydrochloric, hydrobromic, sulphuric and phosphoric acid, with carboxylic acids or with organo-sulphonic acids. Compounds of formulae (IA) and (IB) can also provide pharmaceutically or veterinarily acceptable metal salts, in particular non-toxic alkali metal salts, with bases. Examples include the sodium and potassium salts.
A preferred group of compounds of formulae (IA) and (IB) is that wherein R1 is C1 to C2 alkyl optionally substituted with Het; 2-(morpholin-4-yl)ethyl or benzyl; R2 is C2 to C4 alkyl; R13 is OR3 or NR5R6; R3 is C1 to C4 alkyl optionally substituted with one or two substituents selected from cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, benzyloxy, NR5R6, phenyl, furan-3-yl, pyridin-2-yl and pyridin-3-yl; cyclobutyl; 1-methylpiperidin-4-yl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; R5 and R6 are each independently selected from H and C1 to C2 alkyl optionally substituted with cyclopropyl or methoxy, or, together with the nitrogen atom to which they are attached, form a azetidinyl, pyrrolidinyl or morpholinyl group; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group optionally substituted with one or two methyl groups and optionally in the form of its 4-N-oxide; R10 is H, C1 to C3 alkyl optionally substituted with one or two substituents selected from OH, NR5R6, CONR5R6, phenyl optionally substituted with methoxy, benzodioxol-5-yl and benzodioxan-2-yl; allyl; pyridin-2-yl; pyridin-4-yl or pyrimidin-2-yl; and Het is selected from pyridin-2-yl; 1-oxidopyridin-2-yl; 6-methylpyridin-2-yl; 6-methoxypyridin-2-yl; pyridazin-3-yl; pyrimidin-2-yl and 1-methylimidazol-2-yl.
A more preferred group of compounds of formulae (IA) and (IB) is that wherein R1 is C1 to C2 alkyl optionally substituted with Het; 2-(morpholin-4-yl)ethyl or benzyl; R2 is C2 to C4 alkyl; R13 is OR3; R3 is C1 to C4 alkyl optionally monosubstituted with cyclopropyl, cyclobutyl, OH, methoxy, ethoxy, phenyl, furan-3-yl or pyridin-2-yl; cyclobutyl; tetrahydrofuran-3-yl or tetrahydropyran-4-yl; R7 and R8, together with the nitrogen atom to which they are attached, form a 4-R10-piperazinyl group optionally in the form of its 4-N-oxide; R10 is C1 to C3 alkyl optionally monosubstituted with OH; and Het is selected from pyridin-2-yl; 1-oxidopyridin-2-yl; 6-methylpyridin-2-yl; 6-methoxypyridin-2-yl; pyridazin-3-yl; pyrimidin-2-yl and 1-methylimidazol-2-yl.
Particularly preferred individual compounds of the invention include 3-ethyl-5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethyl-4-oxidopiperazin-1-yisulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-(2-methoxyethoxy)-5-(4-methylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-n-propyl-2-(pyridin-2-yl) methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxyethoxy)pyridin-3-yl]-3-n-propyl-2-(pyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; (+)-3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 3-ethyl-5-[5-(4-ethylpiperazin-1-ylsulphonyl)-2-(2-methoxy-1(R)-methylethoxy)pyridin-3-yl]-2-(6-methylpyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-(6-methoxypyridin-2-yl)methyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one; 5-[2-i-butoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-2,3-diethyl-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7one; and 5-[2-ethoxy-5-(4-ethylpiperazin-1-ylsulphonyl)pyridin-3-yl]-3-ethyl-2-[1-(pyridin-2-yl)ethyl]-2,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one.
According to a further aspect of the present invention there are provided compounds of the formula (IA) and (IB) as defined hereinbefore but wherein R1 is not unsubstituted C1 alkyl; the optional substituent on the C1 alkyl group of R1 is not a substituted phenyl group or a N-linked heterocyclic group; the optional substituent on the C2 or C3 alkyl group of R1 is not phenyl or Het; or wherein R13 is not NR5R6; or wherein the alkyl group of R3 is not C5 or C6; or wherein the optional substituent on R3 is not C3 to C5 cycloalkyl; or wherein neither the alkyl or the optional alkoxy substituents on R3 are terminated by a haloalkyl group; or wherein the C1 to C4 alkyl groups of R5 and R6 are not substituted by C3 to C5 cycloalkyl or C1 to C4 alkoxy; or wherein the C1 to C4 alkyl groups of R5 and R6 do not, together with the nitrogen group to which they are attached form an azetidinyl group; or wherein Het is not a C1 to C4 alkoxy or an HNR15 group.
In a further aspect, the present invention provides processes for the preparation of compounds of formulae (IA) and (IB), their pharmaceutically and veterinarily acceptable salts, and pharmaceutically and veterinarily acceptable solvates of either entity, as illustrated below.
It will be appreciated by persons skilled in the art that, within certain of the processes described, the order of the synthetic steps employed may be varied and will depend inter alia on factors such as the nature of other functional groups present in a particular substrate, the availability of key intermediates and the protecting group strategy (if any) to be adopted. Clearly, such factors will also influence the choice of reagent for, use in the said synthetic steps.
Illustrative of a protecting group strategy is the route to the 2xe2x80x2-(2-hydroxyethoxy) analogue (Example 33), the precursor to which (Example 32) contains benzyl as the alcohol-protecting group.
It will also be appreciated that various standard substituent or functional group interconversions and transformations within certain compounds of formulae (IA) and (IB) will provide other compounds of formulae (IA) and (IB). Examples include alkoxide exchange at the 2-position of the 5-(pyridin-3-yl) substituent (see conversions of Example 1 to Examples 4B, 9, 11, 13, 23, 24, 32 and 64, Example 2 to Example 14, Example 20 to Example 21, Example 26 to Examples 29, 65, 66, 67 and 68, Example 35 to Example 36, Example 38 to Examples 39 and 40, and Example 45 to Example 46), amine exchange at the 2-position of the 5-(pyridin-3-yl) substituent (see conversions of Example 78 to Examples 148 and 154) and piperazine and/or pyridine N-oxidation (see conversions of Example 1 to Example 70, Example 28 to Example 71, and Example 4 to Examples 72 and 73).
The following processes are illustrative of the general synthetic procedures which may be adopted in order to obtain the compounds of the invention.
1. A compound of formula (IA) or (IB) may be prepared from a compound of formula (IIA) or (IIB) respectively: 
wherein Y is halo, preferably chloro, and R1, R2 and R13 are as previously defined for formulae (IA) and (IB), by reaction with a compound of formula (III):
R7R8NHxe2x80x83xe2x80x83(III)
wherein R7 and R8 are as previously defined for formulae (IA) and (IB).
The reaction is generally conducted at from about 0xc2x0 C. to about room temperature, preferably in the presence of an appropriate solvent such as a C1 to C3 alkanol or dichloromethane, using an excess of (III) or other suitable base such as triethylamine to scavenge the acid by-product (HY).
Conveniently, this reaction lends itself to xe2x80x9chigh-speed analogue synthesisxe2x80x9d (HSAS), as illustrated by Examples 203 to 212 in which a particular compound of formula (IIB) is coupled with a range of readily accessible amines of formula (III).
A compound of formula (IIA) or (IIB) may be prepared from a compound of formula (IVA) or (IVB) respectively: 
wherein R1, R2 and R13 are as previously defined for formulae (IIA) and (IIB), by the application of known methods for converting amino to a SO2Y group wherein Y is also as previously defined for formulae (IIA) and (IIB). For example, when Y is chloro, by the action of about a two-fold excess of sodium nitrite in a mixture of concentrated hydrochloric acid and glacial acetic acid at from about xe2x88x9225xc2x0 C. to about 0xc2x0 C., followed by treatment with excess liquid sulphur dioxide and a solution of about a three-fold excess of cupric chloride in aqueous acetic acid at from about xe2x88x9215xc2x0 C. to about room temperature. When R13 contains a primary or secondary amino group, protection of the said amino group with an acid stable group such as acetyl or benzyl will generally be advantageous.
A compound of formula (IVA) or (IVB) may be prepared by cyclisation of a compound of formula (VA) or (VB) respectively: 
wherein R1, R2 and R13 are as previously defined for formulae (IVA) and (IVB). Preferably, the cyclisation is base-mediated, using an alkali metal salt of a sterically hindered alcohol or amine. For example, the required cyclisation may be effected using about a 1.5 to 5, preferably a 3- to 5-fold excess of potassium t-butoxide or potassium bis(trimethylsilyl)amide, optionally in the presence of molecular sieves, in a suitable solvent at the reflux temperature of the reaction mixture, or, optionally in a sealed vessel at about 100xc2x0 C. When R13 is OR3 and an alcohol is selected as solvent, the appropriate alcohol of formula R3OH should be employed in order to obviate potential problems associated with alkoxide exchange at the 2-position of the pyridine ring.
A compound of formula (VA) or (VB) may be prepared by reduction of a compound of formula (VIA) or (VIB) respectively: 
wherein R1, R2 and R13 are as previously defined for formulae (VA) and (VB), by conventional catalytic or catalytic transfer hydrogenation procedures. Typically, the hydrogenation is achieved using a Raney nickel catalyst or a palladium catalyst such as 10% Pd on charcoal, in a suitable solvent such as ethanol at a hydrogen pressure of from about 345 kPa (50 psi) to about 414 kPa (60 psi) at from about room temperature to about 60xc2x0 C., preferably from about 40xc2x0 C. to about 50xc2x0 C.
A compound of formula (VIA) or (VIB) may be prepared by reaction of a compound of formula (VIIA) or (VIIB) respectively: 
wherein R1 and R2 are as previously defined for formulae (VIA) and (VIB) with a compound of formula (VIII): 
wherein R13 is also as previously defined for formulae (VIA) and (VIB). Again, as for (IVA) and (IVB), a conventional amine protecting group strategy is preferred for (VIII) when R13 contains a primary or secondary amino group.
The coupling reaction may be achieved using conventional amide bond-forming techniques, e.g. via the acyl chloride derivative of (VIII) in the presence of up to about a five-fold excess of a tertiary amine such as triethylamine or pyridine to act as scavenger for the acid by-product (HY), optionally in the presence of a catalyst such as 4-dimethylaminopyridine, in a suitable solvent such as dichloromethane, at from about 0xc2x0 C. to about room temperature. For convenience pyridine may also be used as the solvent.
In particular, any one of a host of amino acid coupling variations may be used. For example, the acid of formula (VII) or a suitable salt (e.g. sodium salt) thereof may be activated using a carbodiimide such as 1,3-dicyclohexylcarbodiimide or 1-ethyl-3-(3-dimethylaminoprop-1-yl)carbodiimide optionally in the presence of 1-hydroxybenzotriazole hydrate and/or a catalyst such as 4-dimethylaminopyridine, or by using a halotrisaminophosphonium salt such as bromotris(pyrrolidino)phosphonium hexafluorophosphate or by using a suitable pyridinium salt such as 2-chloro-1-methylpyridinium iodide. Either type of coupling is conducted in a suitable solvent such as dichloromethane or tetrahydrofuran, optionally in the presence of a tertiary amine such as N-methylmorpholine or N-ethyldiisopropylamine (for example when either the compound of formula (VIIA) or (VIIB), or the activating reagent, is presented in the form of an acid addition salt), at from about 0xc2x0 C. to about room temperature. Preferably, from 1 to 2 molecular equivalents of the activating reagent and from 1 to 3 molecular equivalents of any tertiary amine present are employed.
In a further variation, the carboxylic acid function of (VIII) may first of all be activated using up to about a 5% excess of a reagent such as N,Nxe2x80x2-carbonyldiimidazole in a suitable solvent, e.g. ethyl acetate or butan-2-one, at from about room temperature to about 80xc2x0 C., followed by reaction of the intermediate imidazolide with either (VIIA) or (VIIB) at from about 20xc2x0 C. to about 90xc2x0 C.
2. An alternative, generally applicable, synthetic route to compounds of formulae (IA) and (IB) involves the incorporation of the R4 substituent at an earlier stage of the synthesis.
Thus a compound of formula (IA) or (IB) may be prepared by cyclisation of a compound of formula (IXA) or (IXB) respectively: 
wherein R1, R2, R13 and R4 are as previously defined for formulae (IA) and (IB), by analogy with the previously described cyclisation of the compounds of formulae (VA) and (VB).
Alternative reaction conditions are to conduct the reaction with about 1.2 to 4 molecular equivalents of sterically hindered base in a sealed vessel at from about 100xc2x0 C. to about 120xc2x0 C. or, rather than an alcohol of formula R3OH, to use a sterically hindered alcohol, e.g. 3-methylpentan-3-ol, as solvent with about 1.5 to 4.5 molecular equivalents of sterically hindered base, such as potassium t-butoxide or KHMDS, and optionally in a sealed vessel at from about 120xc2x0 C. to about 150xc2x0 C.
A compound of formula (IXA) or (IXB) may be prepared by reaction of a compound of formula (VIIA) or (VIIB) respectively, wherein R1 and R2 are as previously defined for formulae (IXA) and (IXB) with a compound of formula (X): 
wherein R13 and R4 are also as previously defined for formulae (IXA) and (IXB), by analogy with the reactions of (VIIA) or (VIIB) with the nicotinic acid derivatives of formula (VIII) already described. Compounds having the general formula (X) may be prepared directly from compounds having the general formula (VIII) by reduction and subsequent conversion to R4 as detailed previously herein.
3. As mentioned earlier, certain compounds of formulae (IA) and (IB) can be interconverted by inducing alkoxide exchange or displacement at the 2-position of the 5-(pyridin-3-yl) substituent.
(i) When R13 is OR3, this may be achieved, by treating the appropriate alcohol with an alkali metal salt of a sterically hindered alcohol or amine in order to generate the required alkoxide anion which then reacts with the substrate. Typically, in a two-step procedure, a mixture of from about 5 to about 8 molecular equivalents of potassium bis(trimethylsilyl)amide and the required alcohol as solvent is heated at from about 80xc2x0 C. to about 100xc2x0 C. for about 0.5 to 1 hour, followed by addition of the compound of formula (IA) or (IB) and heating of the reaction mixture at from about 100xc2x0 C. to about 120xc2x0 C. Alternatively, in a one-step procedure, the substrate may be treated directly, in the required alcohol as solvent, with from about 1.2 to about 6, preferably from about 4 to about 6 molecular equivalents of, for example, potassium bis(trimethylsilyl)amide or potassium t-butoxide at from about 80xc2x0 C. to about 130xc2x0 C. A further variation employs the required alcohol as solvent, saturated with ammonia, at about 100xc2x0 C. in a sealed vessel.
(ii) When R13 is NR5R6, the substrate may be treated with an excess of R5R6NH, or a suitable acid addition salt thereof, in the presence of an excess of a sterically hindered amine in a suitable solvent. Typically, R5R6NH is used as the free base with about a 3-fold excess (over the substrate) of potassium bis(trimethylsilyl)amide (KHMDS) in dimethylformamide (DMF) as solvent at about 100xc2x0 C. Alternatively, an excess of R5R6NH may be used as the solvent and the reaction conducted in the presence of about a 50% excess of copper(II) sulphate at up to the reflux temperature of the reaction medium. Where the desired amino substituent on the compound of the formula (IA) or (IB) is xe2x80x94NR5R6 and one of either R5 or R6 is H, then the exchange reaction may be carried out by refluxing with the appropriate amine, and copper(II)sulphate penta- or hepta-hydrate or KHDMS in DMF. Typically, to exchange the OR3 group for alternative amines of the formula NHR5R6, such as compounds wherein R5 or R6 are selected from aliphatic or cyclic amines, optionally including oxygen, then the reaction is preferably carried out by treating with the appropriate amine and about 3 equivalents of potassium bis(trimethylsilyl)amide in DMF for about 18 hours at 100xc2x0 C.
4. Clearly, for certain compounds of formulae (IA) and (IB) wherein R13 is OR3, by exploiting the cyclisation and alkoxide exchange methodology described hereinbefore, it may be particularly advantageous to generate a compound of formula (IA) or (IB) from a compound of formula (IXA) or (IXB) respectively, wherein the 2-alkoxy group of the 5-(pyridin-3-yl) substituent in the former is different from that in the latter, directly in a xe2x80x9cone-pot reactionxe2x80x9d.
When the alcohol which is to provide the new 2-alkoxy group is too scarce or expensive to be employed as the reaction solvent, then it will be expedient to use a suitable alternative such as 1,4-dioxan.
5. A further, generally applicable, synthetic route to compounds of formula (IA) and (IB) involves incorporation of the R1 substituent in the final step of the synthesis.
Thus a compound of formula (IA) or (IB) may be prepared by alkylation of a compound of formula (IA) or (IB) wherein R1 is hydrogen and R2, R13 and R4 are as previously defined for formulae (IA) and (IB), using one or more of a plethora of well-known methods, such as:
(i) reaction with a compound of formula R1X, wherein R1 is as previously defined for formulae (IA) and (IB), and X is a suitable leaving group, e.g. halo (preferably chloro, bromo or iodo), C1-C4 alkanesulphonyloxy, trifluoromethanesulphonyloxy or arylsulphonyloxy (such as benzenesulphonyloxy or p-toluenesulphonyloxy), in the presence of an appropriate base, optionally in the presence of sodium iodide or potassium iodide, at from about xe2x88x9270xc2x0 C. to about 100xc2x0 C. Preferably the alkylation is conducted at from about room temperature to about 80xc2x0 C. Suitable base-solvent combinations may be selected from
(a) sodium, potassium or caesium carbonate, sodium or potassium bicarbonate, or a tertiary amine such as triethylamine or pyridine, together with a C1 to C4 alkanol, 1,2-dimethoxyethane, tetrahydrofuran, 1,4-dioxan, acetonitrile, pyridine, dimethylformamide or N,N-dimethylacetamide;
(b) sodium or potassium hydroxide, or a sodium or potassium C1 to C4 alkoxide, together with a C1 to C4 alkanol, water or mixtures thereof;
(c) lithium, sodium or potassium hydride, lithium, sodium or potassium bis(trimethylsilyl)amide, lithium diisopropylamide or butyllithium, together with toluene, ether, 1,2-dimethoxyethane, tetrahydrofuran or 1,4-dioxan; or
(d) under phase transfer catalysis conditions, a tetraalkylammonium halide or hydroxide, together with a mixture of an aqueous solution of sodium or potassium hydroxide and dichloromethane, 1,2-dichloroethane or chloroform:
(ii) reaction with a compound of formula R1OH, wherein R1 is as previously defined for formulae (IA) and (IB), using classical Mitsunobu methodology. Typical reaction conditions involve treating the substrate with the alkanol in the presence of a triarylphosphine and a di(C1 to C4)alkyl azodicarboxylate, in a suitable solvent such as tetrahydrofuran or 1,4-dioxan, at from about xe2x88x925xc2x0 C. to about room temperature.
Typically, about a 10% excess of sodium hydride is added to a solution of the substrate in a suitable solvent, e.g. anhydrous tetrahydrofuran, and the resulting anion treated with about a 10% excess of the required R1X.
A compound of formula (IA) or (IB) wherein R1 is hydrogen and R2, R13 and R4 are as previously defined for formulae (IA) and (IB) may be obtained from a compound of formula (IXA) or (IXB) respectively wherein R1 is hydrogen and R2, R13 and R4 are as previously defined for formulae (IXA) and (IXB), under the same conditions as those used for the conversion of a compound of formula (IXA) or (IXB) to a compound of formula (IA) or (IB) respectively when R1 is other than hydrogen, followed by acidification of the reaction mixture to a pH of about 6.
The amines of formula (III), the 4-aminopyrazole-5-carboxamides of formulae (VIIA) and (VIIB), the carboxylic acids of formulae (VIII) and (X), the nitrites of formula (XIII) and the esters of formula (XVI), when neither commercially available nor subsequently described, can be obtained either by analogy with the processes described in the Preparations section or by conventional synthetic procedures, in accordance with standard textbooks on organic chemistry or literature precedent, from readily accessible starting materials using appropriate reagents and reaction conditions.
Moreover, persons skilled in the art will be aware of variations of, and alternatives to, those processes described hereinafter in the Examples and Preparations sections which allow the compounds defined by formulae (IA) and (IB) to be obtained.
The pharmaceutically acceptable acid addition salts of the compounds of formulae (IA) and (IB) which contain a basic centre may also be prepared in a conventional manner. For example a solution of the free base is treated with the appropriate acid, either neat or in a suitable solvent, and the resulting salt isolated either by filtration of by evaporation under vacuum of the reaction solvent.
Pharmaceutically acceptable base addition salts can be obtained in an analogous manner by treating a solution of a compound of formula (IA) or (IB) with the appropriate base. Both types of salt may be formed or interconverted using ion-exchange resin techniques.
The biological activities of the compounds of the present invention were determined by the following test methods.
Phosphodiesterase (PDE) Inhibitory Activity
In vitro PDE inhibitory activities against cyclic guanosine 3xe2x80x2,5xe2x80x2-monophosphate (cGMP) and cyclic adenosine 3xe2x80x2,5xe2x80x2-monophosphate (cAMP) phosphodiesterases were determined by measurement of their IC50 values (the concentration of compound required for 50% inhibition of enzyme activity).
The required PDE enzymes were isolated from a variety of sources, including human corpus cavernosum, human and rabbit platelets, human cardiac ventricle, human skeletal muscle and bovine retina, essentially by the method of W. J. Thompson and M. M. Appleman (Biochem., 1971, 10, 311). In particular, the cGMP-specific PDE (PDE5) and the cGMP-inhibited cAMP PDE (PDE3) were obtained from human corpus cavernosum tissue, human platelets or rabbit platelets; the cGMP-stimulated PDE (PDE2) was obtained from human corpus cavernosum; the calcium/calmodulin (Ca/CAM)-dependent PDE (PDE1) from human cardiac ventricle; the cAMP-specific PDE (PDE4) from human skeletal muscle; and the photoreceptor PDE (PDE6) from bovine retina.
Assays were performed using a modification of the xe2x80x9cbatchxe2x80x9d method of W. J. Thompson et al. (Biochem., 1979, 18, 5228). Results from these tests show that the compounds of the present invention are potent and selective inhibitors of cGMP-specific PDE5.
Functional Activity
This was assessed in vitro by determining the capacity of a compound of the invention to enhance sodium nitroprusside-induced relaxation of precontracted rabbit corpus cavernosum tissue strips, as described by S. A. Ballard et al. (Brit. J. Pharmacol., 1996, 118 (suppl.), abstract 153P).
In Vivo Activity
Compounds were screened in anaesthetised dogs to determine their capacity, after i.v. administration, to enhance the pressure rises in the corpora cavernosa of the penis induced by intracavernosal-injection of sodium nitroprusside, using a method based on that described by Trigo-Rocha et al. (Neurourol. and Urodyn., 1994, 13, 71).
In human therapy, the compounds of formulae (IA) and (IB), their pharmaceutically acceptable salts, and pharmaceutically acceptable solvates of either entity, can be administered alone, but will generally be administered in admixture with a pharmaceutical carrier selected with regard to the intended route of administration and standard pharmaceutical practice. Preferably, they are administered orally in the form of tablets containing such excipients as starch or lactose, or in capsules or ovules either alone or in admixture with excipients, or in the form of elixirs, solutions or suspensions containing flavouring or colouring agents. They can also be injected parenterally, for example intracavernosally, intravenously, intramuscularly or subcutaneously. For parenteral administration, they are best used in the form of a sterile aqueous solution which may contain other substances, for example enough salts or monosaccharides to make the solution isotonic with blood. For buccal or sublingual administration they may be administered in the form of tablets or lozenges which can be formulated in a conventional manner. The compounds may also be administered intranasally or formulated for dermal application.
For oral, parenteral, buccal and sublingual administration to patients, the daily dosage level of the compounds of formulae (IA) and (IB) and their pharmaceutically acceptable salts and solvates may be from 10 to 500 mg (in single or divided doses). Thus, for example, tablets or capsules may contain from 5 to 250 mg of active compound for administration singly, or two or more at a time, as appropriate. The physician in any event will determine the actual dosage which will be most suitable for an individual patient and it will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case; there can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention. The skilled person will also appreciate that, in the treatment of certain conditions (including MED and FSD), compounds of the invention may be taken as a single dose on an xe2x80x9cas requiredxe2x80x9d basis (i.e. as needed or desired).
Generally, in humans, oral administration of the compounds of the invention is the preferred route, being the most convenient and, for example in MED, avoiding the well-known disadvantages associated with intracavernosal (i.c.) administration. A preferred oral dosing regimen in MED for a typical man is from 25 to 250 mg of compound when required. In circumstances where the recipient suffers from a swallowing disorder or from impairment of drug absorption after oral administration, the drug may be administered parenterally, sublingually or buccally.
For veterinary use, a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, is administered as a suitably acceptable formulation in accordance with normal veterinary practice and the veterinary surgeon will determine the dosing regimen and route of administration which will be most appropriate for a particular animal.
Thus the invention provides a pharmaceutical composition comprising a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, together with a pharmaceutically acceptable diluent or carrier.
It further provides a veterinary formulation comprising a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, together with a veterinarily acceptable diluent or carrier.
The invention also provides a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, or a pharmaceutical composition containing any of the foregoing, for use as a human medicament.
In addition, it provides a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, or a veterinary formulation containing any of the foregoing, for use as an animal medicament.
In yet another aspect, the invention provides the use of a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate of either entity, for the manufacture of a human medicament for the curative or prophylactic treatment of a medical condition for which a cGMP PDE5 inhibitor is indicated. There is further provided the use of a compound of formula (IA) or (IB) or a suitable salt or solvate thereof, in the manufacture of a medicament for the treatment of a medical condition in which inhibition of a cGMP PDE5 is desirable.
It also provides the use of a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate of either entity, for the manufacture of an animal medicament for the curative or prophylactic treatment of a medical condition for which a cGMP PDE5 inhibitor is indicated.
Moreover, the invention provides the use of a compound of formula (IA) or (IB), or a pharmaceutically acceptable salt thereof, or a pharmaceutically acceptable solvate containing either entity, for the manufacture of a human medicament for the curative or prophylactic treatment of male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction. incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension. pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency, (e.g. post transluminal coronary angioplasty (post-PTCA)), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility (e.g. irritable bowel syndrome (IBS)). Other conditions which may be mentioned include pre-eclampsia, Kawasaki""s syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy. stroke, Alzheimer""s disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure and hypoxic vasoconstriction. Particularly preferred conditions include MED and FSD.
It also provides the use of a compound of formula (IA) or (IB), or a veterinarily acceptable salt thereof, or a veterinarily acceptable solvate containing either entity, for the manufacture of an animal medicament for the curative or prophylactic treatment of Male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency (e.g. post-PTCA), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility (e.g. IBS). Other conditions which may be mentioned include pre-eclampsia, Kawasaki""s syndrome, nitrate tolerance, multiple sclerosis, peripheral diabetic neuropathy, stroke, Alzheimer""s disease, acute respiratory failure, psoriasis, skin necrosis, cancer, metastasis, baldness, nutcracker oesophagus, anal fissure and hypoxic vasoconstriction. Particularly preferred conditions include MED and FSD.
Additionally, the invention provides a method of treating or preventing a medical condition for which a cGMP PDE5 inhibitor is indicated, in a mammal (including a human being), which comprises administering to said mammal a therapeutically effective amount of a compound of formula (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, or a pharmaceutical composition or veterinary formulation containing any of the foregoing.
Still further, the invention provides a method of treating or preventing male erectile dysfunction (MED), female sexual dysfunction (FSD), premature labour, dysmenorrhoea, benign prostatic hyperplasia (BPH), bladder outlet obstruction, incontinence, stable, unstable and variant (Prinzmetal) angina, hypertension, pulmonary hypertension, congestive heart failure, atherosclerosis, stroke, peripheral vascular disease, conditions of reduced blood vessel patency (e.g. post PTCA), chronic asthma, bronchitis, allergic asthma, allergic rhinitis, glaucoma or diseases characterised by disorders of gut motility in a mammal (including a human being), which comprises administering to said mammal a therapeutically effective amount of a compound of formula (IA) or (IB), or a pharmaceutically or veterinarily acceptable salt thereof, or a pharmaceutically or veterinarily acceptable solvate of either entity, or a pharmaceutical composition or veterinary formulation containing any of the foregoing.
The invention also includes any novel intermediates described herein, for example those of formulae (IIA), (IIB), (IVA), (IVB), (IXA), (IXB), (VA) and (VB).